Peripheral benzodiazepine receptor (PBR) is expressed in most organs and its expression is reported to be increased in activated microglia in the brain which are the smallest type of glial cells acting as the immune cells of the central nervous system (CNS). Microglia are related to other phagocytic cells including macrophages and dendritic cells. Microglia are thought to be highly mobile cells that play numerous important roles in protecting the nervous system. They are also thought to play a role in neurodegenerative disorders such as Alzheimer's disease, dementia, multiple sclerosis and Amyotrophic lateral sclerosis. Microglia are responsible for producing an inflammatory reaction to insults (J. Neuroinflammation, 2004, Jul 30; 1(1):14.), The C-11 isotope labeled version of PK11195 (1) has been widely used for the in vivo imaging of neuroinflamation and PBRs, but its signal in the brain was not high enough for stable quantitative analysis.

Furthermore, it has been shown that the development of superior positron-emitting ligands, like [11C]DAA1106 (2) (e.g. Eur J. Pharmacol. 1999 Apr. 29; 371(2-3):197-204 and Life Sci. 1999; 64(16):1455-64) and [18F]fluoroethyl-DAA1106 (3) (e.g. J. Nucl. Med., (2006), 47, 43-50), for visualization of PBRs is possible: The compounds 2 and 3 have a higher binding affinity to PBR and a higher accumulation in the brain than [11C]PK11195 (1).

The non-radioactive version of compound 2 is claimed by the patent family related to WO99/006353, whereas the compound 3 is claimed by the patent family related to U.S. Pat. No. 6,870,069.
Compound 3 can be synthesized by the alkylation reaction of the phenol DAA1123 (4) with [18F]-1-bromo-2-fluoro-ethane (5) as shown in FIG. 6. The drawback of the reaction is that the reagent [18F]-1-bromo-2-fluoro-ethane (5) has to be synthesized from trifluoro-methanesulfonsäure-2-bromo-ethyl ester (6) prior phenol alkylation (4→3). Due to the fact that the 18F isotope has a half-life of only 111 min it is a challenge to produce [18F]-1-bromo-2-fluoro-ethane (5) just in time and to carry out the subsequent alkylation in good yield. The overall radiochemical yield for this two-step sequence shown in FIG. 6 is normally lower than 10% yield.
Attempts have been made to synthesize compound 3 directly by starting from tosylate 7 (J. Med. Chem., (2004), 2228) by 18F labeling in a one-step procedure, (see FIG. 7). The reaction was carried out between 80° C. and 120° C. However, the radiochemical yields were not reproducible (2%-60%). In addition purification of [18F]-(3) from reaction mixture was often difficult since many of the impurities resulting from the target and reaction greatly reduced the efficiency (J. Med. Chem., (2004), 2228).
It is known from literature (Biorg. Med. Chem., (2004), 12, 423) that compound 7 can be prepared from 4 by alkylation of 1,2-bis-tosyloxy-ethane which is commercially available (see FIG. 8).
Compound 4 is prepared from benzyl ether 8 by catalytic hydrogenation (see FIG. 9). Benzyl ether 8 is prepared in a one-pot reaction from nitro compound 9 and aldehyde 10 (see FIG. 10) Nitro compound 9 is synthesized from difluoride (11) and phenol by nucleophilic aromatic substitution reaction. Whereas compound 10 is prepared from phenol 12 and benzyl bromide (see FIG. 11) It would be useful to have a practical and sufficient technique for the synthesis of 18F-(3) in only one rather than in two radiochemical steps, The profile of by-products needs to be simple enough so that the desired product 18F-(3) can be purified easily, In addition it would be useful to have convenient synthetic routes to compounds and intermediates which allow the one-step labeling towards 18F-(3).